Cyclosporin

Cyclosporin

[1 capsule $6.77]

ADMINISTRATION ROUTES:

  • PO, IV

ALTERNATIVE NAMES:

  • Neoral, Sandimmun

ICU INDICATIONS:

  • It is unusual for this medication to be commenced in the ICU. Patients admitted to the intensive care unit may be on cyclosporin at the time of admission for the following indications:
    1. Solid organ transplant rejection prophylaxis
    2. Bone marrow transplant rejection prophylaxis
    3. inflammatory disorders such as rheumatoid arthritis,uveitis and psoriasis

      Note: decisions about indications and dosage of cyclosporin in ICU patients should be made in consultation with the relevant specialty team (eg renal, haematology etc)

PRESENTATION AND ADMINISTRATION:

  • IV:
    Sandimmun injection is a concentrate that must be diluted prior to IV infusion. It is an oily, faintly yellow coloured solution that contains polyoxyethylated castor oil 65% w/v, ethanol 33% v/v and with air in ampoules replaced by nitrogen
    Dilute the concentrate 1:20 to 1:100 by volume (eg 50mg in 20-100ml) with compatible IV fluid. Ensure concentrate is well mixed in diluent fluid to reduce risk of an initial bolus of heavier non-solubilised polyoxyethylated castor oil, which carries an increased risk of anaphylactoid reactions. Diluted solution for infusion is clear and oily. Visually inspect infusion concentrated and infusion solution for particulate matter and / or discolouration. Administer diluted infusion solution over 2-6 hours
    Compatible with normal saline and 5% glucose
    Use glass containers or 5% glucose in EXCEL containers (non PVC)
    Do not mix with other fluids or medications
    Discard any remaining concentrate after preparation of required dose
    Discard any diluted fluid not used within 24 hours of preparation
    Store at room temperature. Protect from light.
  • PO:
    Neoral 25mg, 50mg and 100mg capsules
    Neoral oral solution (100mg/ml)

DOSAGE:

  • Dosing should be titrated based on clinical assessments of rejection and tolerability and is generally directed by the primary team responsible for the transplant (eg haematology, renal etc)
  • IV:
    Dose varies according to indication but is generally in the range of 1-5mg/kg/day
  • PO:
    Dosage varies according to indication but is generally in the range of 3-15mg/kg/day

    Note: Recommended IV dosage is approximately 1/3rd oral dosage
    See Laboratory Tests for information about therapeutic drug monitoring which is mandatory

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

  • Dose reduction is generally required and is based on therapeutic drug monitoring (see Laboratory Tests for information about therapeutic drug monitoring)

DOSAGE IN PAEDIATRICS:

  • Seek specialist paediatric advice

CLINICAL PHARMACOLOGY:

  • Cyclosporin is a potent immunosuppressive agent that prolongs survival of allogeneic transplants involving kidney, liver, heart, pancreas, bone marrow, small intestine, and lung.

CONTRAINDICATIONS:

  1. hypersensitivity to cyclosporin
  2. uncontrolled hypertension
  3. malignancy

WARNINGS

  • Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the degree of immunosuppression in patients treated with cyclosporin.
  • Cyclosporin can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporin therapy.
  • Cyclosporin can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses.

PRECAUTIONS

  • General:
    During treatment with cyclosporin, vaccination may be less effective; and the use of live attenuated vaccines should be avoided.
  • Laboratory Tests:
    Cyclosporin has a narrow therapeutic index and variable pharmacokinetics and so monitoring of therapy is mandatory in the critically ill. It is usually appropriate to monitor levels twice weekly.
    Two strategies are used for monitoring, one based on trough sampling, i.e. the concentration of drug found within 1 hour before the next dose (termed C0), and the other on the concentration of drug found 2 hours after the dose is given (termed C2).
    C0 sampling has been widely used although it appears that C0 is only a weak indicator of absorption of drug. Moreover, the results are assay-dependent as samples of this type contain a large proportion of metabolite that may interfere.
    C2 sampling is advantageous in that C2 is an acceptable surrogate for absorption (measured as the area under the concentration-time curve). Moreover, most of the measured drug found at this time is parent drug, making the measurement relatively free of interference from metabolites. A disadvantage of C2 is the need for samples to be taken close to the 2-hour time-point (+ or -15 minutes).
    Factors affecting the target ranges for treatment include time of sampling (C0 or C2), organ transplanted, time since transplantation, and other medications. More specific recommended target concentrations for transplant patients are as follows. They may vary in individual cases on the basis of age, gender, renal function, number of episodes of rejection, and concomitant immunosuppressive medication.

    Target trough (C0) ranges are as follows:
    Liver:
    Induction: 225-300 ng/mL
    Maintenance: 100-150 ng/mL
    Heart:
    Induction: 250-325 ng/mL
    Maintenance: 125-175 ng/mL
    Kidney:
    Induction: 150-225 ng/mL
    Maintenance: 100-180 ng/mL
    Bone Marrow:
    Induction: 95-205 ng/mL
    Maintenance: 95-205 ng/mL
    Autoimmune indications:
    Induction: 150-200 ng/mL
    Maintenance: 100-150 ng/mL

    Target C2 ranges are as follows:
    Liver:
    0-3 months post transplant: 800-1200 ng/mL
    3-6 months post transplant:  640-960 ng/mL
    >6 months post transplant: 480-720 ng/mL
    Renal:
    1 months post transplant: 1360-2040 ng/mL
    2 months post transplant: 1200-1800 ng/mL
    3 months post transplant: 1040-1560 ng/mL
    4-6 months post transplant: 880-1320 ng/mL
    7-12 months post transplant: 720-1080 ng/mL
    >12 months post transplant: 640-960   ng/mL
    Lung:
    0-2 days post transplant: >800,
    1-7 days post transplant: 1200
    1-4 weeks post transplant: 1200-1700
    2 months post transplant: 1000-1500
    3 months post transplant: 800-1200
    4-6 months post transplant: 700-1000
    7-12 months post transplant: 600-900
    >12 months post transplant: 600-800

    Note: samples for trough (C0) therapeutic monitoring should be collected in an EDTA (Mauve tube) taken one hour before the next dose is due; samples for C2 monitoring should be taken 2 hours +/-15 minutes after the most recent dose

  • Drug/Laboratory Test Interactions:
    Nil of note

IMPORTANT DRUG INTERACTIONS FOR THE ICU

  • All of the individual drugs cited below are well substantiated to interact with cyclosporine
  • Drugs That May Potentiate Renal Dysfunction
    Antibiotics: Gentamicin, tobramycin, vancomycin, trimethoprim with sulfamethoxazole.
    Antineoplastics: Melphalan. Antifungals: Amphotericin B, ketoconazole.
    Anti-Inflammatory Drugs: Azapropazon, diclofenac, naproxen, sulindac, colchicine.
    Gastrointestinal Agents: Cimetidine, ranitidine.
    Immunosuppressives: Tacrolimus.
  • Drugs That Alter Cyclosporin Concentrations
    Cyclosporin is extensively metabolized cytochrome P-450 3A. Substances that inhibit this enzyme could decrease metabolism and increase cyclosporin concentrations. Substances that are inducers of cytochrome P-450 activity could increase metabolism and decrease cyclosporin concentrations. Monitoring of circulating cyclosporin concentrations and appropriate dosage adjustment are essential when these drugs are used concomitantly.
  • Drugs That Increase Cyclosporin Concentrations:
    Calcium Channel Blockers: Diltiazem, nicardipine, verapamil.
    Antifungals: Fluconazole, itraconazole, ketoconazole.
    Antibiotics: Clarithromycin, erythromycin, quinupristin/daldopristin.
    Glucocorticoids: Methylprednisolone.
    Other Drugs: Allopurinol, bromocriptine, danazol, metoclopramide, colchicine, amiodarone.
    The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporin, however no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly.
  • Drugs/Dietary Supplements That Decrease Cyclosporin Concentrations:
    Antibiotics: Nafcillin, rifampin.
    Anticonvulsants: Carbamazepine, phenobarbital, phenytoin.
    Other Drugs: Octreotide, ticlopidine, orlistat, St. John’s Wort.
  • Other Drug Interactions:
    Cyclosporin may reduce the clearance of digoxin, colchicine, prednisolone and HMG- CoA reductase inhibitors (statins).
    Severe digitalis toxicity has been seen within days of starting cyclosporin in several patients taking digoxin.
    There are also reports on the potential of cyclosporin to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction.
    Cyclosporin should not be used with potassium-sparing diuretics because hyperkalemia can occur.

ADVERSE REACTIONS

  • Central nervous system:
    Tremor, convulsions, headache, paresthesia
  • Cardiovascular system:
    Hypertension, arrhythmia
  • Gastrointestinal system:
    Stomatitis, gum hyperplasia, diarrhoea, nausea/vomiting, hepatotoxicity, abdominal discomfort
  • Haematological system:
    Leukopenia, Lymphoma
  • Urogenital system:
    Renal failure
  • Endocrine system:
    Hirsutism, Gynecomastia
  • Musculoskeletal system:
    Cramps
  • Metabolic system:
    Hypomagnesemia

Critical Care Drug Manual

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